Adenocarcinoma of the lower esophagus develops almost exclusively in patients with Barrett""s esophagus (BE), a condition characterized by the presence of metaplastic columnar epithelium. While the prognosis of patients diagnosed with adenocarcinoma is poor, the chances of successful treatment increase significantly if the disease is detected at the dysplastic stage. The surveillance of patients with BE for dysplasia is challenging in two respects. First, dysplasia is not visible during routine endoscopy. Thus, numerous random biopsies are required. Second, the histopathologic diagnosis of dysplasia is problematic, as there is poor inter-observer agreement on the classification of a particular specimen, even among expert gastrointestinal pathologists. Optical techniques, such as fluorescence, may significantly enhance the endoscopist""s ability to detect these early dysplastic changes in BE. Indeed, fluorescence spectroscopy studies using exogenous fluorophores, such as Photofrin(copyright) and aminolevulinic-acid induced protoporphyrin IX, show that there is a significant difference between the measured red fluorescence of the carcinomatous and non-dysplastic tissue as a result of the preferential accumulation of the drug. Initial autoflorescence spectroscopy studies performed at 410 nm excitation report promising results for detecting high-grade dysplasia. However, focal high-grade and low-grade lesions could not be detected reliably. Thus a continuing need exists for further improvements in the optical measurements used to detect early stage carcinomas.
The present invention relates to a combination of spectroscopic systems that can improve the sensitivity and accuracy of dysplasia detection in patients with BE. Fluorescence, reflectance and light scattering spectroscopies provide complementary information about the biochemical, architectural and morphological state of tissue and the corresponding changes that occur during the progression of dysplasia. A system has been developed providing for combining these three methods to provide for detection, mapping, and/or imaging of tissue. A preferred embodiment of the invention utilizes this trimodal system to guide a biopsy procedure.
Of importance in this system for real time measurements is the simultaneous or near simultaneous collection of light from the same spot or region of interest. The detected diffuse reflectance spectrum is processed to remove a diffusive background component. This is accomplished by measuring a component of the light that is periodic in wavelength. This component arises from the light that is Mie-scattered by surface epithelial cell nuclei, for example. By analyzing the amplitude and frequency of the periodic structure, the density and size distribution of these nuclei can be extracted. For the reflectance, light scattered and fluorescence components to be properly correlated and used to assess a given region of interest, there is preferably substantial overlap of the excitation light for both the reflectance and fluorescence measurements. The reflected light is used to both correct the fluorescence spectrum and to generate a light scattered spectrum based on the use of the periodic structure contained therein. The apparatus delivers both excitation components to the region of interest through the same distal surface of the probe, preferably through the same optical fiber of collection of fibers.
The biopsy channel of an endoscope can be used to insert the fiber optic light delivery and collection system used to obtain measurements. Alternatively, a small diameter endoscope, 5 mm or less in diameter for example, can include the light delivery and collection system suitable for many applications. A preferred embodiment of the system can use a single fiber system for delivery and collection, or alternatively central delivery fiber and six collection fibers concentrically arranged around the delivery fiber. The proximal end of the light delivery and collection probe is optically coupled to both a broadband flash lamp and a monochromatic source such as a laser. A rotating filter or dye wheel can be used to rapidly switch the excitation wavelength over a selected range.
The need for using reflected light arises from the need to correct for the effects of hemoglobin absorption on the measured integrated tissue fluorescence intensity. The combination of fluorescence and reflectance spectroscopies can be applied to remove distortions introduced by scattering and absorption into the entire measured tissue fluorescence spectrum. The undistorted or modified fluorescence spectrum can serve as a sensitive indicator of tissue biochemistry, while reflectance and light scattering spectroscopies provide morphological information on tissue architecture and epithelial cell nuclei. The present invention can include the simultaneous use of all three spectroscopic methods for characterizing tissue and diagnosing disease. The following demonstrates that the combined use of all three techniques provides improved results as compared to the results of each technique individually, in terms of detecting not only high-grade, but also low-grade dysplastic changes in BE, for example.